DESCRIPTION: (From Applicant's Abstract) The investigators are interested in the rational development of therapies that might either help repair or prevent damage to the visual system caused by disease or injury. Thus, it is important to understand both the ways the way the visual system responds to injury and the molecular mechanisms that damage the retina. The investigators propose studies of both FGF, a neuroprotective agent, and nitric oxide (NO), a potent neurotoxin, in ischemic damage, in photodamage, and in traumatic injury. They originally purified FGF from the retina as a molecule capable of stimulating neural differentiation. The FGFs can regulate the survival and differentiation of several cells in the PNS and CNS, including the retina. The investigators showed that there is are dramatic changes in the localization of FGF in response to injury to the optic nerve. In the first part of the application, the investigators will focus on the functional involvement of FGF and NO in two models of damage to the retina, photodamage and ischemic damage. The investigators' laboratory was the first to show that FGF can protect neurons is by making them resistant to NO, which is produced during excitotoxicity. The investigators have recently demonstrated that the RPE expresses a constitutively active form of Nitric Oxide Synthase in vivo. The investigators propose the hypothesis that NO may be a toxic agent that contributes to neural damage during ischemia or photodamage. FGF may confer resistance to NO toxicity by several mechanisms. In Aim 1, the investigators explore the hypothesis that FGF can protect photoreceptors against photodamage by conferring resistance to nitric oxide toxicity. The investigators will determine if NO is toxic to photoreceptors and they will determine if FGF protects by reducing the level of Nitric Oxide Synthase in vivo or by making photoreceptors more resistant to NO. In Aim 2, the investigators will develop and characterize a new model of retinal ischemia based on the four vessel occlusion model and use it (or the established IOP model of retinal ischemia) to determine whether ischemia induces the expression of either FGF of NOS in the retina. The investigators will also determine if generation of NO plays an important role in ischemic or excitotoxic death in the retina. In Aim 3, the investigators propose to determine which cells are responsible for the change in FGF expression after injury.This is a first step to determining how traumatic damage regulates the level of FGF in the retina. The investigators will also determine if damaging the optic nerve causes changes in the distribution of aFGF. By considering both the role of NO as a toxic agent and FGF as a protective agent, the investigators hope to be able to understand how the retina responds to damaging situations with the expectation that this knowledge may be a guide to therapeutic intervention. The information the investigators obtained will be of fundamental importance to pathologies that involve ischemia or excitotoxicity including occlusive vascular diseases, glaucoma, and vasoproliferative disorders.